DE2638850C2 - 2-Amino-N? 1? - (1-phenyl-2-methyl-2-propyl) propionic acid amides, processes for their preparation and pharmaceuticals containing them - Google Patents

Description

a compound of the general formula
CH ₃ O

<ξ, ^ -CH ₂ -C-NH-C-CH-HaI R ~

(ID

CH ₃

CH ₃

wherein Hal is Cl or Br, reacts with ammonia or b) an N-carbobenzoxyalanine amide of the general formula

CH ₃ OO

I Il Il

CH ₂ -C-NH-C-CH-NH-CO-CH ₂ -

I I

CH ₃ CH ₃

(HD

catalytically hydrogenated and the process products of reactions a) and b) optionally converted into their pharmacologically acceptable acid addition salts.

4. Medicaments containing at least one 2-amino-N '- (1-phenyl-2-methyl-2-propyl) propionic acid amide according to claim 1 and 2, optionally together with a pharmaceutically acceptable carrier or diluent.

The most widely used compound currently used to control depression is Imipramine of the formula

(Tf

CH ₂ CH ₂ CH ₂ N (CHj) ₂

This connection is mood-lifting and psychomotor activating, but it has different ones Disadvantage. It is anticholinergic and causes anticholinergic symptoms such as dryness in the mouth, Tremor, tachycardia, and sweating. In high doses it can seriously cause cardiac arrhythmias, and even in normal doses it can have toxic interactions in people with heart defects cause. In addition, another disadvantage of treatment with imipramine is the late onset of the antidepressant effect, and this effect is only observable after about three weeks of treatment.

It has been shown that imipramine has an effect on the action of carrier substances in the central nervous system Has. More specifically, imipramine inhibits the accumulation mechanism for norepinephrine (NA) and 5-hydroxytripytamine (5-HT). The mood-enhancing part of the antidepressant effect is arguably mainly related to the inhibition of 5-HT accumulation.

The object of the invention is to find compounds having an effect on the central nervous system, in particular with anti-depressive aclivitiil and with reduced frequency of side effects as well as with increased effectiveness compared to the funds currently used in this area.

This object is achieved according to the invention with new 2-amino-N '- (1-phenyl-2-methyl-2-propyl) -Dropionsüurcamiden the general formula

CH ₃ O

I Il

CH ₂ -C -NH-C-CH-NH ₂

I I

CH ₃ CH ₃

(D

wherein R represents a hydrogen atom, chlorine atom, bromine atom, methyl group, trifluoromethyl group or methoxy group means, and pharmacologically acceptable acid addition salts dissolved therefrom. These connections can be used to selectively reduce the central accumulation of 5-hydroxytryptamine in neurons inhibit. In addition, the cardiac toxicities for these new compounds are much weaker than those of Imipramine.

Since they contain an asymmetric carbon, they exist in optically active forms and can after methods known per se are separated into their optical antipodes, such as by using optical active acids such as tartaric acid, camphor-10-sulfonic acid or dibenzoyltartaric acid.

The group R is preferably in the para position. Preferred substituents R are chlorine, bromine or Methyl, especially in the para position.

The following compounds can be mentioned as examples of compounds according to the invention:

2-Amino-N '- [3- (4-chlorophenyl) -2-methyl-2-propyl] propionic acid amide,

2-Amino-N '- [3- (4-bromophenyl) -2-methyl-2-propyl] propionic acid amide,

2-Amino-N '- [3- (4-methylphenyl) -2-methyl-2-propyl] propionic acid amide,

2-Amino-N ^l - [3- (4-trifluoromethylphenyl) -2-methyl-2-propyl] propionic acid amide,

2-Amino-N '- [3- (3-methylphenyl) -2-methyl-2-propyl] propionic acid amide and

2-Amino-N '- [3-phenyl-2-methyl-2-propyl] propionic acid amide.

The compounds according to the invention can each be prepared in a manner known per se

a) by reacting a compound of the general formula

CH ₃ O

-CH ₂ -C-NH-C-CH-Hal (II)

I I

CH ₃ CH ₃

where Hai is chlorine or bromine, with ammonia or

b) by catalytic hydrogenation of an N-carbobenzoxyalanine amide of the general formula

CH ₃ OO

CH ₂ -C — NH-C —CH-NH-C —O —CH ₂ - <f> (III)

ι ι ^ = /

CH ₃ CH ₃

getting produced.

The reactions according to a) or b) are preferably carried out in an inert organic solvent which is able to dissolve the reactants. Preferably, the reactions at atmospheric pressure or superatmospheric pressure at a temperature between -10 and 100 ^0C, preferably performed between 0 and 30 ⁰ C.

The intermediates of the formulas II and III are new compounds.

The intermediates of the formula II can be prepared by reacting a compound of the general formula

CH ₃

CH ₂ -C -NH ₂ CH ₃

with a compound of the general formula O

Il

Hai —C —CH-Hai
CH ₃

(V)

10

15th

20th

25th

30th

35

40

45

50

(IV) 55

60

65

be prepared, where R and Hai have the above meanings.
The intermediates of the formula III can by reacting a compound of the formula IV with a

Compound of the general formula

HOOC - CH- NH- C - O - CH ₂ - <ζ ~ \ < ^Πί >

CH ₃

be prepared in the presence of dicyclohexylcarbodiimide.

The new compounds according to the invention can therapeutically as racemic mixtures of (+) - and (-) - forms which are usually obtained in the synthesis can be used. But you can also after known methods can be separated into the optically active forms, which are also used in therapy can be used. If desired, the optically active modification can be made by direct synthesis are, for example, via an optically active compound of the formula VI, as described above became.

In clinical practice, the compounds of the invention will normally be administered orally, rectally or by mouth Injection administered in the form of pharmaceutical preparations containing the active ingredient either as free Base or as a pharmaceutically acceptable, non-toxic acid addition salt, such as hydrochloride, hydrobromide, Lactate, acetate, phosphate, sulfate, sulfamate, citrate, tartrate or oxalate, in conjunction with a pharmaceutical compatible carrier material. So if here from the new connections after the In the invention, in general or specifically, this is intended to include both the free amine base and its acid addition salts unless the context in which these terms are used is as in the specific examples do not allow such a broad meaning. The carrier material can be a solid, semi-solid or liquid diluent or a capsule. These pharmaceutical preparations that range from 0.1 to 95 Containing% by weight of the active substance constitute a further aspect of the invention. Usually the active substance makes 0.5 to 20% by weight for preparations for injection and 2 to 50% by weight for preparations for oral administration.

To produce pharmaceutical preparations containing a compound according to the invention in the form of dosage units for oral administration, the selected compound can be mixed with a solid powdery Carrier material, such as lactose, sucrose, sorbitol, mannitol, starch, such as potato starch, corn starch or Amylopectin, cellulose derivatives, a binder such as gelatin or polyvinylpyrrolidone, and a Lubricants such as magnesium stearate, calcium stearate, polyethylene glycol waxes and the like are mixed and then compressed into tablets. If coated tablets or dragees are required, the Dragee cores produced as above with a concentrated sugar solution, which also contain gum, for example arabic, gelatin, talc, titanium dioxide or the like can be coated. Instead you can The tablets, cores or dragee cores can also be coated with a varnish that is highly volatile organic solvent or solvent mixture is dissolved. Dyes can these coatings can be added to easily between tablets of different active substances or different Differentiate amounts of active compounds.

For the production of soft gelatin capsules (pearl-shaped closed capsules) made from gelatin and for example The active substance can consist of glycerine, or to produce similar closed capsules mixed with a vegetable oil. Hard gelatin capsules can contain granules of the active substance i η Combination with solid, powdery carrier materials such as lactose, sucrose, sorbitol, mannitol, starches (such as potato starch, corn starch or amylopectin), cellulose derivatives or gelatine.

Dosage units for rectal administration can be prepared in the form of suppositories, which comprise the active substance in admixture with a neutral fat base, or as. Gelatin rectal capsules, comprising the active substance mixed with vegetable oil or paraffin oil.

Liquid preparations for oral administration can be made in the form of syrups or suspensions such as in the form of solutions containing about 0.2 to 20% by weight of those described herein contain active substance, the remainder being made up of sugar and a mixture of ethanol, water, and glycerin Propylene glycol. If necessary, such liquid preparations can contain colorants, flavorings, Contains saccharin and carboxymethyl cellulose as thickeners.

Solutions for parenteral administration by injection can be used as an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substance, preferably at a concentration of about 0.5 to 10% by weight. These solutions can also contain stabilizers and / or buffering agents and conveniently withdrawn in different dosage units on ampoules.

Suitable daily doses of the compounds according to the invention for therapeutic treatment are 100 to 500 mg for oral administration and 20 to 100 mg for parenteral administration.
The particularly preferred compound according to the invention is 2-amino-N '- [3- (4-chlorophenyl) -2-methyl-2-propyl-propionic acid amide of the formula

CH ₃ O

CI-V ^ V-CH ₂ -C-NH-C-CH-NH ₂ (GEA 609)

X = / I I

CH ₃ CH ₃

Preferably this compound is prepared and used in the form of its hydrochloride salt.

example
Preparation of 2-amino-N '- [3- (4-chlorophenyl) -2-methyl-2-propyl] propionic acid amide

Method a

3- (4-Chlorophenyl) -2-methyl-2-propylamine (IV) was obtained according to a known method [Farmaco (Pavia) Ed. Sci., 15, p. 337 (1960), G. Ferrari].

The amine IV (30.0 g, 0.163 mol) was dissolved in toluene (140 ml) and a 10% sodium hydroxide solution (200 ml). The mixture was 8UF-S ⁰ CgCkUhIt, and 2-bromopropionyl bromide (62.2 g, 0.288 mol) was added dropwise over 20 minutes with vigorous stirring of the biphasic system. Stirring was continued at room temperature for two hours. After filtration and washing of the precipitate with water and toluene, the white product of 2-bromo-N- [3- (4-chlorophenyl) -2-methyl-2-propyl] propionic acid amide (II) was dried in vacuo. Yield: 48.4 g (93%), mp 122-123 ° C.

Compound II (10.0 g, 0.031 mol) was dissolved in absolute ethanol (250 ml). The solution was chilled in ice and saturated with ammonia gas (5 hours). The total time for the amination was 6 days at room temperature and the saturation with NH ₃ -GaS was repeated once a day. The solvent was removed in vacuo. The remaining oil was dissolved in ether (100 ml) and the solution was extracted with 0.5 hydrochloric acid (100 ml). The acidic phase was made alkaline with 1N sodium hydroxide solution (pH 10) and extracted twice with ether. After drying and evaporation, a colorless oil was obtained from which the hydrochloride was prepared. After recrystallization from chloroform and ethyl acetate, the yield of 2-amino-N '- [3- (4-chlorophenyl) -2-methyl-2-propyl) propionic acid amide hydrochloride was 5.2 g (57%). F. = 180 to 181 ° C.

Method B.

N-carbobenzoxyalanine (4.5 g, 0.020 mol) was dissolved in methylene chloride (45 ml) and cooled on ice. Dicyclohexylcarbodiimide (4.1 g, 0.020 mol) was added in portions with stirring and this was allowed for 15 minutes continued. A thick white precipitate was obtained. This mixture was added over 10 minutes a solution of 3- (4-chlorophenyl) -2-methyl-2-propylamine (IV) (see method A) (3.7 g, 0.020 mol) in Methylene chloride (10 ml) added. Stirring was continued at room temperature for 1.5 hours. That The mixture was filtered and the filtrate washed with water, 3N hydrochloric acid and saturated sodium hydrogen carbonate solution and saturated sodium chloride solution. Drying and evaporation of the organic phase gave a viscous colorless oil (7.2 g, 93%).

The carbobenzoxy protected product (III) (7.0 g, 0.018 mol) was dissolved in a 0.2 N solution of hydrochloric acid in absolute ethanol (150 ml) and the solution was cooled on ice. Nitrogen gas was bubbled through the solution and palladium on carbon (5%, 2.0 g) was added. Cooling and stirring under a nitrogen atmosphere was continued for 10 minutes. Hydrogen gas was then bubbled into the mixture for 3 hours. After the reaction, the excess hydrogen was removed by a stream of nitrogen (15 minutes). The catalyst was filtered off and the filtrate evaporated in vacuo to give a white crystalline product which was recrystallized from ethyl acetate. F. = 180 to 181 ^° C., yield: 4.3 g (83%) of the desired 2-amino-N '- [3- (4-chlorophenyl) -2-methyl-2-propyl] propionic acid amide hydrochloride.

45 Pharmacological Methods

A. Biochemical experiments

Inhibition of the accumulation of carbon-14-labeled 5-HT and tritiated noradrenal in vitro and in vivo

The method is described by Ross, Renyi and Ögren in European Journal of Pharmacology 17 (1972), pages 107 bis

112 described. Tricyclic antidepressants of the imipramine type, which are added in vitro or in vivo to mouse ·

sen decreased the accumulation of ^I4 C-5-HT and ³ H-NA in vitro. In the experiments in 55 κ

In vitro, different concentrations of the test compound were added to the incubation medium. At ;

The experiments in vivo were given different doses of the test substance intraperitoneally 1/2 hour before the $

Killing the animals administered. The incubation was the same in both types of experiments, i.e. the midbrain %

was taken out, cut into slices and incubated in a mixture containing 100 mg of brain slice each

ben from 0.2 η mol of ¹⁴ C-5-HT, 0.2 η mol of ³ H-NA and 11 mol glucose in 2 ml Krebs-Henseleit buffer of pH 7.4 60 |

duration. The incubation time was 5 minutes. The accumulation of radioactive amines in the brain discs {

was dissolved in Soluene 350 (trademark of Packard), and the amounts were determined according to the double mar- j

kierungstechnik determined by liquid scintillation. The 50% decrease in active accumulation results in |

Ending dose (ED ₅₀ ) was determined graphically from the curves in which dose versus response to- jjj

was carried. Active accumulation is defined as that part of radioactivity uptake that is 65 |

high levels of cocaine are inhibited. All doses were given to at least four animals. §

B. Pharmacological experiments

5-HTP response potentiation test

The inhibition of the accumulation of 5-HT potentiates the effects of administered 5-hydroxytryptophan (5-HTP), probably by increasing the amount of 5-HT at the receptor. Three mice received the Test compounds 1 hour (or 4 to 24 hours) before dl-5 HTP. 90 mg / kg i.v. v. 5-HTP alone only yields one weak behavioral syndrome, but a characteristic behavioral syndrome can be seen in previously treated mice, that occurs within 5 minutes: tremor, lordosis, abduction of the hind paws, head beating. The severity of the syndrome is rated from 0 to +3. Each group consisted of three animals, and at least four Groups were given 25 mg / kg i.p. p. tested. As a comparison control groups were used, the imipramine received because imipramine constantly potentiates dl-5-HTP. The smallest dose of the test compound, the maximum Evaluation (+3) for all animals is determined from a logarithmic dose response curve and in the referred to as the "effective dose" in the following table.

The results of the tests described above are compiled in the table below. The designation "GEA 609" means the compound according to the invention 2-amino-N ¹ - [3- (4-chlorophenyi) -2-methyl-2-propyl] propionic acid amide hydrochloride.

5-HT = 5-hydroxytryptamine, 1X10 ⁷ M.
NA = 1-noradrenaline, 1 x ItT ⁷ M.
5-HTP = 5-hydroxytryptophan.
ip = intraperitoneal administration.

Evaluation of the results obtained in the pharmacological tests

The compound of the invention blocks the accumulation of 5-hydroxytryptamine in brain slices in vitro and in vivo, but does not inhibit norepinephrine accumulation. In vivo it is more effective than Imipramine as inhibitors of 5-hydroxytryptamine. It potentiates the reactions of 5-Hydroxytryptophan with much lower doses than imipramine.

The results show that the new compound is much more selective than imipramine in inhibiting the There is accumulation of 5-hydroxytryptamine.

The following examples illustrate the production of pharmaceutical preparations with compounds according to the invention. The following recipes were used to make tablets:

2-Amino-N- [3- (4-chlorophenyl) -2-methyl-2-propyl] - 50 g propionic acid amide hydrochloride 85 g Lactose 40 g Potato starch 5g Polyvinyl pyrrolidone 18 g Cellulose 2g Magnesium stearate 2-Amino-N '- [3- (4-chlorophenyl) -2-methyl-2-propyl] - 100 g propionic acid amide hydrochloride 90 g Lactose 50 g Potato starch 5g Polyvinyl pyrrolidone 23 g Cellulose 2g Magnesium stearate

1000 tablets were prepared from the above compositions, each 50 mg and 100 mg of the active substance contained. If necessary, the tablets obtained can be coated with a film, such as with methyl cellulose in an organic solvent.

Tabel inhibition
in vitro
5-HT ¹ )
^ g / ml) (50%) of the accumulation
NA ² ) in vivo
5-HT ² )
(mg / kg ip) NA ² )
(mg / kg ip) Exponentiation
from 5-HTP ³ )
effective dose
(mg / kg ip) m
iS
I. link 0.7
0.1 10
0.06 20th
24 > 40
6th 0.5
15th I. GEA 609
Imipramine

Claims (3)

Patent claims: 1. 2-Amino-N ¹ - (1-phenyl-2-methyl-2-propyl) propionic acid amides of the general formula CH ₃ O <£ ~ \ - CH ₂ - C - NH - C _{- CH - NH 2} R ~~ CH ₃ CH ₃ wherein R is a hydrogen atom, chlorine atom, bromine atom, methyl group, trifluoromethyl group or Methoxygrappe means, and their pharmacologically acceptable acid addition salts. 2. 2-Amino-N ¹ - (i-phenyl-2-methyl-2-propyl> propionic acid amide according to claim 1, wherein R is in the para position and denotes a chlorine atom or a methyl group, and their pharmacologically acceptable acid addition salts. 3. A process for the preparation of the 2-amino-N ¹ - (l-phenyl-2-methyl-2-propyl) propionic acid amides according to Claim 1 and 2, characterized in that in each case one is carried out in a manner known per se